Single-use Duodenoscope: The Cleaner Standard.

Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard in the endoscopic management of biliary disease. An average of 700,000 ERCPs are performed every year, and most are performed using a reusable flexible duodenoscope. The innovation of disposable duodenoscopes has changed the dynamic in the advanced endoscopy field of study to primarily reduce or eliminate the risk of cross-contamination between patients. Many factors affect whether institutions can convert from standard reusable duodenoscopes to single-use duodenoscopes including the cost of the devices, reimbursement from insurance companies for the new devices, and the overall environmental impact. However, the reduction of cross-contamination leading to active infection in patients, environmental waste produced with high-level disinfection procedures, staff and equipment required for reprocessing, and the inability to frequently upgrade duodenoscopes for optimal performance are all factors that favor transitioning to single-use duodenoscopes. As these devices are new to the field of gastroenterology, the purpose of this review is to analyze the advantages and disadvantages of transitioning to single-use devices and a brief mention of alternative options for institutions unable to make this change.

Scintigraphy of Gastrointestinal Motility: Best Practices in Assessment of Gastric and Bowel Transit in Adults.

Various radiologic examinations and other diagnostic tools exist for evaluating gastrointestinal diseases. When symptoms of gastrointestinal disease persist and no underlying anatomic or structural abnormality is identified, the diagnosis of functional gastrointestinal disorder is frequently applied. Given its physiologic and quantitative nature, scintigraphy often plays a central role in the diagnosis and treatment of patients with suspected functional gastrointestinal disorder. Most frequently, after functional gallbladder disease is excluded, gastric emptying scintigraphy (GES) is considered the next step in evaluating patients with suspected gastric motility disorder who present with upper gastrointestinal symptoms such as dyspepsia or bloating. GES is the standard modality for detecting delayed gastric emptying (gastroparesis) and the less commonly encountered clinical entity, gastric dumping syndrome. Additionally, GES can be used to assess abnormalities of intragastric distribution, suggesting specific disorders such as impaired fundal accommodation or antral dysfunction, as well as to evaluate gastric emptying of liquid. More recently, scintigraphic examinations for evaluating small bowel and large bowel transit have been developed and validated for routine diagnostic use. These can be performed individually or as part of a comprehensive whole-gut transit evaluation. Such scintigraphic examinations are of particular importance because clinical assessment of suspected functional gastrointestinal disorder frequently fails to accurately localize the site of disease, and those patients may have motility disorders involving multiple portions of the gastrointestinal tract. The authors comprehensively review the current practice of gastrointestinal transit scintigraphy, with diseases and best imaging practices illustrated by means of case review. ©RSNA, 2024 See the invited commentary by Maurer and Parkman in this issue.

What's important in a contract beyond the salary? A primer for pain physicians and trainees.

This manuscript is designed to complement the previously published primer on salary structures for new pain physicians. The previous manuscript "Employment Contract Financial Models for the Pain Physician: A Primer" had a goal of increasing understanding of financial models by pain fellows when preparing for contract negotiations. This manuscript illustrates the many equally important considerations of "non-monetary" values that are a significant part of contract negotiation outside of salary. It contributes to the overall education for trainees and pain physicians on benefits and job responsibilities.

Donor HLA mismatch promotes full donor T-cell chimerism in the allogeneic stem cell transplant with reduced-intensity conditioning and post-transplant cyclophosphamide GVHD prophylaxis.

Full donor T-cell chimerism (FDTCC) after allogeneic stem cell transplant (allo-SCT) has been associated with improved outcomes in hematologic malignancy. We studied if donor human leukocyte antigen (HLA) mismatch improves achievement of FDTCC because mismatched HLA promotes donor T-cell proliferation where recipient T-cells had been impaired by previous treatment. Patients (N = 138) received allo-SCT with reduced-intensity conditioning (RIC) from 39 HLA mismatched donors (16 unrelated; 23 haploidentical) with post-transplant cyclophosphamide (PTCy) or 99 matched donors (21 siblings; 78 unrelated) with PTCy (N = 18) or non-PTCy (N = 81). Achievement of FDTCC by day 100 was higher with HLA mismatched donors than matched donors (82.1% vs. 27.3%, p < 00,001), which was further improved with 200 cGy total body irradiation (87.9%) or lymphoid (versus myeloid) malignancy (93.8%). Since all mismatched transplants used PTCy, FDTCC was higher with PTCy than non-PTCy (68.4% vs. 25.7%, p < 0.00001), but not in the matched transplant with PTCy (38.9%), negating PTCy as the primary driver. Lymphocyte recovery was delayed with PTCy than without (median on day + 30: 100 vs. 630/µL, p < 0.0001). The benefit of FDTCC was not translated into survival outcomes, especially in myeloid malignancies, possibly due to the insufficient graft-versus-tumor effects from the delayed lymphocyte recovery. Further studies are necessary to improve lymphocyte count recovery in PTCy transplants.

Predictive Partition Dosimetry and Outcomes after Yttrium-90 Resin Microsphere Radioembolization of Colorectal Cancer Metastatic to the Liver: A Retrospective Analysis.

PURPOSE: To characterize estimated absorbed tumor dose (ADT), objective response (OR), and estimated target dose of liver metastatic colorectal cancer (mCRC) after resin microsphere yttrium-90 (90Y) radioembolization using partition dosimetry. MATERIALS AND METHODS: In this retrospective, single-center study, multicompartment dosimetry of index tumors undergoing 90Y radioembolization from October 2013 to July 2022 was performed using MIM SurePlan and pretreatment technetium-99m macroaggregated albumin infusion data. Thirty-eight patients with mCRC underwent treatments for 59 index tumors. Patients were imaged every 2-3 months after treatment and then every 3-6 months after disease control to determine the best response per Response Evaluation Criteria in Solid Tumors 1.1. Responses were categorized as OR or nonresponse (NR). A Cox proportional hazards model evaluated the probability of tumor OR and local progression-free survival (LPFS) based on ADT. RESULTS: Patients had a median follow-up of 116 days (interquartile range [IQR], 69-231 days). The ADT was higher for OR patients than for NR patients (median, 130.8 [IQR, 85.6-239.0] vs 40.6 [IQR, 26.0-66.3] Gy; P < .001). A greater percentage of OR than NR patients were treated with activities calculated by partition modeling (54% vs 12%; P = .005). Only ADT predicted response (P = .032). At 6 months, an ADT of 120 Gy predicted a 55% (95% CI, 0.0%-89%) probability of OR. Only ADT (P = .010) and female sex (P = .014) predicted LPFS. At 1 year, an ADT of 120 Gy predicted a 70% (95% CI, 35%-100%) probability of LPFS. CONCLUSIONS: Tumor dose was the strongest predictor of OR for mCRC. Administration of an estimated 120 Gy to mCRC predicted 55% OR with 90Y resin microspheres at 6 months.

Identification and Characterization of Synthetic Nicotine Product Promotion and Sales on Instagram Using Natural Language Processing.

INTRODUCTION: There has been a rapid proliferation of synthetic nicotine products in recent years, despite newly established regulatory authority and limited research into its health risks. Previous research has implicated social media platforms as an avenue for nicotine product unregulated sales. Yet, little is known about synthetic nicotine product content on social media. We utilized natural language processing to characterize the sales of synthetic nicotine products on Instagram. METHODS: We collected Instagram posts by querying Instagram hashtags (e.g., "#tobaccofreenicotine) related to synthetic nicotine. Using BERT, collected posts were categorized into thematically related topic clusters. Posts within topic clusters relevant to study aims were then manually annotated for variables related to promotion and selling (e.g., cost discussion, contact information for offline sales). RESULTS: A total of 7,425 unique posts were collected with 2,219 posts identified as related to promotion and selling of synthetic nicotine products. Nicotine pouches (52.9%, n=1174), ENDS (30.6%, n=679), and flavored e-liquids (14.1%, n=313) were most commonly promoted. 16.1% (n=345) of posts contained embedded hyperlinks and 5.8% (n=129) provided contact information for purported offline transactions. Only 17.6% (n=391) of posts contained synthetic nicotine specific health warnings. CONCLUSIONS: In the United States, synthetic nicotine products can only be legally marketed if they have received premarket authorization from the FDA. Despite these prohibitions, Instagram appears to be a hub for potentially unregulated sales of synthetic and "tobacco-free" products. Efforts are needed by platforms and regulators to enhance content moderation and prevent unregulated online sales of existing and emerging synthetic nicotine products. IMPLICATIONS: There is limited clinical understanding of synthetic nicotine's unique health risks and how these novel products are changing over time due to regulatory oversight. Despite synthetic nicotine specific regulatory measures, such as the requirement for premarket authorization and FDA warning letters issued to unauthorized sellers, access to and promotion of synthetic nicotine is widely occurring on Instagram, a platform with over 2 billion users and one that is popular among youth and young adults. Activities include direct-to-consumer sales from questionable sources, inadequate health warning disclosure, and exposure with limited age restrictions, all conditions necessary for the sale of various tobacco products. Notably, the number of these Instagram posts increased in response to the announcement of new FDA regulations. In response, more robust online monitoring, content moderation, and proactive enforcement is needed from platforms who should work collaboratively with regulators to identify, report, and remove content in clear violation of platform policies and federal laws. Regulatory implementation and enforcement should prioritize digital platforms as conduits for unregulated access to synthetic nicotine products and other future novel and emerging tobacco products.

Applying topic modelling and qualitative content analysis to identify and characterise ENDS product promotion and sales on Instagram.

BACKGROUND: Increased public health and regulatory scrutiny concerning the youth vaping epidemic has led to greater attention to promotion and sales of vaping products on social media platforms. OBJECTIVES: We used unsupervised machine learning to identify and characterise sale offers of electronic nicotine delivery systems (ENDS) and associated products on Instagram. We examined types of sellers, geographic ENDS location and use of age verification. METHODS: Our methodology was composed of three phases: data collection, topic modelling and content analysis. We used data mining approaches to query hashtags related to ENDS product use among young adults to collect Instagram posts. For topic modelling, we applied an unsupervised machine learning approach to thematically categorise and identify topic clusters associated with selling activity. Content analysis was then used to characterise offers for sale of ENDS products. RESULTS: From 70 725 posts, we identified 3331 engaged in sale of ENDS products. Posts originated from 20 different countries and were roughly split between individual (46.3%) and retail sellers (43.4%), with linked online sellers (8.8%) representing a smaller volume. ENDS products most frequently offered for sale were flavoured e-liquids (53.0%) and vaping devices (20.5%). Online sellers offering flavoured e-liquids were less likely to use age verification at point of purchase (29% vs 64%) compared with other products. CONCLUSIONS: Instagram is a global venue for unregulated ENDS sales, including flavoured products, and access to websites lacking age verification. Such posts may violate Instagram's policies and US federal and state law, necessitating more robust review and enforcement to prevent ENDS uptake and access.

An unsupervised machine learning approach for the detection and characterization of illicit drug-dealing comments and interactions on Instagram.

Background: Growing use of social media has led to the emergence of virtual controlled substance and illicit drug marketplaces, prompting calls for action by government and law enforcement. Previous studies have analyzed Instagram drug selling via posts. However, comments made by users involving potential drug selling have not been analyzed. In this study, we use unsupervised machine learning to detect and classify prescription and illicit drug-related buying and selling interactions on Instagram. Methods: We used over 1,000 drug-related hashtags on Instagram to collect a total of 43,607 Instagram comments between February 1st, 2019 and May 31st, 2019 using data mining approaches in the Python programming language. We then used an unsupervised machine learning approach, the Biterm Topic Model (BTM), to thematically summarize Instagram comments into distinct topic groupings, which were then extracted and manually annotated to detect buying and selling comments. Results: We detected 5,589 comments from sellers, prospective buyers, and online pharmacies from 531 unique posts. The vast majority (99.7%) of comments originated from drug sellers and online pharmacies. Key themes from comments included providing contact information through encrypted third-party messaging platforms, drug availability, and price inquiry. Commonly offered drugs for sale included scheduled controlled substances such as Adderall and Xanax, as well as illicit hallucinogens and stimulants. Comments from prospective buyers of drugs most commonly included inquiries about price and availability. Conclusions: We detected prescription controlled substances and other illicit drug selling interactions via Instagram comments to posts. We observed that comments were primarily used by sellers offering drugs, and typically not by prospective buyers interacting with sellers. Further research is needed to characterize these "social" drug marketplace interactions on this and other popular social media platforms.

How Much Will My Child's ACL Reconstruction Cost? Availability and Variability of Price Estimates for Anterior Cruciate Ligament Reconstruction in the United States.

BACKGROUND: Despite recent policy efforts to increase price transparency, obtaining estimated prices for surgery remains difficult for most patients and families. PURPOSE: Assess availability and variability of cost and self-pay discounts for pediatric anterior cruciate ligament (ACL) reconstruction in the United States. METHODS: This was a prospective study using scripted telephone calls to obtain price estimates and self-pay discounts for pediatric ACL reconstruction. From July to August 2020, investigators called 102 hospitals, 51 "top-ranked" pediatric orthopaedic hospitals and 51 "non-top ranked" hospitals randomly selected, to impersonate the parent of an uninsured child with a torn ACL. Hospital, surgeon, and anesthesia price estimates, availability of a self-pay discount, and number of calls and days required to obtain price estimates were recorded for each hospital. Hospitals were compared on the basis of ranking, teaching status, and region. RESULTS: Only 31/102 (30.3%) hospitals provided a complete price estimate. Overall, 52.9% of top-ranked hospitals were unable to provide any price information versus 31.4% of non-top-ranked hospitals ( P =0.027). There was a 6.1-fold difference between the lowest and highest complete price estimates (mean estimate $29,590, SD $14,975). The mean complete price estimate for top-ranked hospitals was higher than for non-top-ranked hospitals ($34,901 vs. $25,207; P =0.07). The mean complete price estimate varied significantly across US region ( P =0.014), with the greatest mean complete price in the Northeast ($41,812). Altogether, 38.2% hospitals specified a self-pay discount, but only a fraction disclosed exact dollar or percentage discounts. The mean self-pay discount from top-ranked hospitals was larger than that of non-top-ranked hospitals ($18,305 vs. $9902; P =0.011). An average of 3.1 calls (range 1.0 to 12.0) over 5 days (range 1 to 23) were needed to obtain price estimates. CONCLUSION: Price estimates for pediatric sports medicine procedures can be challenging to obtain, even for the educated consumer. Top-ranked hospitals and hospitals in the Northeast region may charge more than their counterparts. In all areas, self-pay discounts can be substantial if they can be identified but they potentially create an information disadvantage for unaware patients needing to pay out-of-pocket. STUDY DESIGN: Economic; Level of Evidence II. WHAT IS KNOWN ABOUT THE SUBJECT: Previous studies have highlighted the importance of value-based health care decisions and deficits of price transparency in various fields including pediatric and orthopaedics procedures. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE: This study is the first to examine availability and variability of health care cost in pediatric sports medicine and the first to assess availability and magnitude of self-pay discounts, setting expectations for the uninsured patient incurring large out-of-pocket expenses.

Toxic and metabolic leukoencephalopathies in emergency department patients: a primer for the radiologist.

One of the most common chief complaints in the emergency department (ED) is altered mental status (AMS). Imaging plays a critical role in triaging patients and identifying the etiology of AMS. Toxic and metabolic etiologies are one of the primary differential categories for AMS, leading to toxic leukoencephalopathies. Toxic leukoencephalopathies are white matter disorders that result from either exogenous or endogenous sources. Common exogeneous causes of toxic leukoencephalopathy include drugs of abuse (heroin and cocaine), alcohol, inhaled gases (carbon monoxide), industrial agents (pesticides, toluene, ethylene glycol), and neurotoxic medications (methotrexate, metronidazole, vigabatrine, etc.); endogenous causes include hyper- and hypoglycemia, hyperammonemia, hyponatremia, and uremia. The imaging findings of toxic leukoencephalopathies manifest through a combination of vasogenic and cytotoxic edema, resulting in white matter patterns. These white matter patterns have been found to be pathognomonic. In the ED setting, it is imperative to develop a diagnosis based off of the imaging due to the lack of history and context that is typically provided with a chief complaint of altered mental status (AMS). To offer expeditious and accurate diagnosis, we present the classic imaging features of toxic leukoencephalopathies and correlate these imaging findings with pathophysiology.

One-pot synthesis of carboxymethyl-dextran coated iron oxide nanoparticles (CION) for preclinical fMRI and MRA applications.

Superparamagnetic iron-oxide nanoparticles are robust contrast agents for magnetic resonance imaging (MRI) used for sensitive structural and functional mapping of the cerebral blood volume (CBV) when administered intravenously. To date, many CBV-MRI studies are conducted with Feraheme, manufactured for the clinical treatment of iron-deficiency. Unfortunately, Feraheme is currently not available outside the United States due to commercial and regulatory constraints, making CBV-MRI methods either inaccessible or very costly to achieve. To address this barrier, we developed a simple, one-pot recipe to synthesize Carboxymethyl-dextran coated Iron Oxide Nanoparticles, namely, "CION", suitable for preclinical CBV-MRI applications. Here we disseminate a step-by-step instruction of our one-pot synthesis protocol, which allows CION to be produced in laboratories with minimal cost. We also characterized different CION-conjugations by manipulating polymer to metal stoichiometric ratio in terms of their size, surface chemistry, and chemical composition, and shifts in MR relaxivity and pharmacokinetics. We performed several proof-of-concept experiments in vivo, demonstrating the utility of CION for functional and structural MRI applications, including hypercapnic CO2 challenge, visual stimulation, targeted optogenetic stimulation, and microangiography. We also present evidence that CION can serve as a cross-modality research platform by showing concurrent in vivo optical and MRI measurement of CBV using fluorescent-labeled CION. The simplicity and cost-effectiveness of our one-pot synthesis method should allow researchers to reproduce CION and tailor the relaxivity and pharmacokinetics according to their imaging needs. It is our hope that this work makes CBV-MRI more openly available and affordable for a variety of research applications.

Improved outcome in AML relapse after allogeneic transplant with high-intensity chemotherapy followed by 2nd allogeneic stem cell transplant or donor lymphocyte infusion.

Acute myeloid leukemia (AML) relapse after allogeneic stem cell transplant (alloSCT) remains a major therapeutic challenge. While patients with longer remission after initial alloSCT are recommended to receive cell therapy (CT) such as 2ndalloSCT or donor lymphocyte infusion (DLI), survival for patients who relapse within 6 months of alloSCT has been dismal. We evaluated the outcomes of AML relapse after alloSCT to assess the impact of different treatments on long-term survival. One hundred and seventy-two patients with AML underwent alloSCT at the Penn State Cancer Institute from January 2014 to August 2019. Sixty-nine patients relapsed (median age, 60 years; range, 10-75). Of these, 4 patients underwent 2ndalloSCT, and 26 received DLI. One-year overall survival (OS) in all cases was 20.3% (95% CI: 11.8-30.4%). Patients with ECOG performance status (PS) 0-2 at relapse showed a better 1-year OS than those with PS 3-4. Median OS for patients who received chemotherapy only or chemotherapy with CT was 74 or 173.5 days, respectively (p < 0.001). Relapsed patients receiving conventional re-induction chemotherapy were categorized as the high-intensity chemotherapy (H) group, while those receiving treatments such as hypomethylating agents or targeted agents were categorized as the low-intensity chemotherapy (L) group. The H group showed a better 1-year OS compared with the L group. Patients who received H + CT showed a better 1-year OS of 52.9% than the other 3 groups (p < 0.001). Even for patients with post-alloSCT remission duration of less than 6 months, the statistical significance was preserved. Factors including age, donor source at 1stalloSCT, time to relapse, blast counts, PS at relapse, and treatment type after post-alloSCT relapse were used for a multivariate analysis, and matched or mismatched related donor and H + CT after alloSCT were identified as independent factors associated with OS. These findings support the use of H + CT as the treatment option of choice for AML patients who relapse after alloSCT when feasible.

Characterization of Pediatric Breast Abscesses and Optimal Treatment: A Retrospective Analysis.

BACKGROUND: Literature on pediatric breast abscesses is sparse; therefore, treatment is based on adult literature which has shifted from incision and drainage (I&D) to needle aspiration. However, children may require different treatment due to different risk factors and the presence of a developing breast bud. We sought to characterize pediatric breast abscesses and compare outcomes. MATERIALS AND METHODS: A retrospective review of patients presenting with a primary breast abscess from January 2008 to December 2018 was conducted. Primary outcome was persistent disease. Antibiotic utilization, treatment required, and risk factors for abscess and recurrence were also assessed. A follow-up survey regarding scarring, deformity, and further procedures was administered. Fisher's exact and Kruskal-Wallis tests for group comparisons and multivariable regression to determine associations with recurrence were performed. RESULTS: Ninety-six patients were included. The median age was 12.8 y [IQR 4.9, 14.3], 81% were women, and 51% were African-American. Most commonly, patients were treated with antibiotics alone (47%), followed by I&D (27%), and aspiration (26%). Twelve patients (13%) had persistent disease. There was no difference in demographic or clinical characteristics between those with persistent disease and those who responded to initial treatment. The success rates of primary treatment were 80% with antibiotics alone, 90% with aspiration, and 96% with I&D (P = 0.35). The median time to follow-up survey was 6.5 y [IQR 4.4, 8.5]. Four patients who underwent I&D initially reported significant scarring. CONCLUSIONS: Treatment modality was not associated with persistent disease. A trial of antibiotics alone may be considered to minimize the risk of breast bud damage and adverse cosmetic outcomes with invasive intervention.

First-in-human experience of the Bashir Endovascular Catheter in the treatment of iliocaval deep vein thrombosis.

Deep vein thrombosis (DVT) is a common disorder affecting approximately 900,000 new patients in the United States each year. Although the mainstay of treatment of DVT patients is therapeutic anticoagulation, some patients remain significantly symptomatic and therefore require more advanced interventions such as catheter-directed thrombolysis (CDT). We describe a case series of 13 patients with acute symptomatic inferior vena cava (IVC) and iliofemoral DVT that were treated with CDT using the Bashir Endovascular Catheter (BEC). We report the first-in-human use of BEC, which is a novel pharmacomechanical thrombolysis device. All the treated patients had complete and rapid resolution of their symptoms with excellent venous outflow. Despite initial promising results, larger studies using this catheter design will be needed to assess the role of BEC-directed therapy on rates of post-thrombotic syndrome and bleeding complications.

Pulsed Radiofrequency Ablation: An Alternative Treatment Modality for Radiation-Induced Brachial Plexopathy.

Radiation therapy is used as a form of treatment for various neoplastic diseases. There are many potential adverse effects of this therapy, including radiation-induced neurotoxicity. Radiation-induced brachial plexopathy (RIBP) may occur due to the fibrosis of neural and perineural soft tissues, leading to ischemic damage of the axons and Schwann cells. The dose of radiation exceeds 55 Gy in many patients who develop symptoms [1]. Current incidence in the United States is 1-2%, and RIBP is most commonly seen in patients who have undergone treatment for breast cancer, lung cancer, or lymphoma [1-3]. Common symptoms include numbness, paresthesia, dysesthesia, and occasional numbness of the arm. Pain is present in the shoulder and proximal arm and is typically mild to moderate in severity. Diagnosis is often made based on clinical presentation and evaluation of imaging to rule out concurrent malignant etiologies of the brachial plexus. Current recommended treatment includes physical therapy and medical management with anticonvulsants, tricyclic antidepressants, and selective serotonin-norepinephrine reuptake inhibitors.

Overcoming the acquired resistance to gefitinib in lung cancer brain metastasis in vitro and in vivo.

In our previous work, PC-9-Br, a PC-9 brain seeking line established via a preclinical animal model of lung cancer brain metastasis (LCBM), exhibited not only resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib in vitro, but also chemotherapy regimens of cisplatin plus etoposide in vivo. Using this cell line, we investigated novel potential targeted therapeutics for treating LCBM in vitro and in vivo to combat drug resistance. Significant increases in mRNA and protein expression levels of Bcl-2 were found in PC-9-Br compared with parental PC-9 (PC-9-P), but no significant changes of Bcl-XL were observed. A remarkable synergistic effect between EGFR-TKI gefitinib and Bcl-2 inhibitors ABT-263 (0.17 ± 0.010 µM at 48 h and 0.02 ± 0.004 µM at 72 h), or ABT-199 (0.22 ± 0.008 µM at 48 h and 0.02 ± 0.001 µM at 72 h) to overcome acquired resistance to gefitinib (> 0.5 µM at 48 h and 0.10 ± 0.007 µM at 72 h) in PC-9-Br was observed in MTT assays. AZD9291 was also shown to overcome acquired resistance to gefitinib in PC-9-Br in MTT assays (0.23 ± 0.031 µM at 48 h and 0.03 ± 0.008 µM at 72 h). Western blot showed significantly decreased phospho-Erk1/2 and increased cleaved-caspase-3 expressions were potential synergistic mechanisms for gefitinib + ABT263/ABT199 in PC-9-Br. Significantly decreased protein expressions of phospho-EGFR, phospho-Akt, p21, and survivin were specific synergistic mechanism for gefitinib + ABT199 in PC-9-Br. In vivo studies demonstrated afatinib (30 mg/kg) and AZD9291 (25 mg/kg) could significantly reduce the LCBM in vivo and increase survival percentages of treated mice compared with mice treated with vehicle and gefitinib (6.25 mg/kg). In conclusion, our study demonstrated gefitinib + ABT263/ABT199, afatinib, and AZD9291 have clinical potential to treat LCBM.

Surgical Data Recording Technology: A Solution to Address Medical Errors?

: Reducing preventable medical errors remains a universal goal, yet implementing effective solutions remains a challenge. The development of surgical data recording technology shows promise to generate robust qualitative and quantitative data in the surgical theater. These data can allow physicians and their teams to capture specific sources of error and implement corrective interventions. Surgical data recording technology encompasses rudimentary data tabulation on notecards, to integrated audio-video systems containing cameras, microphones, and sensors, capturing and synthesizing intraoperative, environmental, and instrumentation information, along with devices tailored to robotic surgical systems. There is growing interest in the implementation of such technology in medical centers, particularly in the United States, Canada, and Europe, but existing medicolegal and regulatory challenges necessitate further research and clinical assessment in order for this technology to facilitate improved surgical patient safety.

Biological nitrogen fixation in maize: optimizing nitrogenase expression in a root-associated diazotroph.

Plants depend upon beneficial interactions between roots and root-associated microorganisms for growth promotion, disease suppression, and nutrient availability. This includes the ability of free-living diazotrophic bacteria to supply nitrogen, an ecological role that has been long underappreciated in modern agriculture for efficient crop production systems. Long-term ecological studies in legume-rhizobia interactions have shown that elevated nitrogen inputs can lead to the evolution of less cooperative nitrogen-fixing mutualists. Here we describe how reprogramming the genetic regulation of nitrogen fixation and assimilation in a novel root-associated diazotroph can restore ammonium production in the presence of exogenous nitrogen inputs. We isolated a strain of the plant-associated proteobacterium Kosakonia sacchari from corn roots, characterized its nitrogen regulatory network, and targeted key nodes for gene editing to optimize nitrogen fixation in corn. While the wild-type strain exhibits repression of nitrogen fixation in conditions replete with bioavailable nitrogen, such as fertilized greenhouse and field experiments, remodeled strains show elevated levels in the rhizosphere of corn in the greenhouse and field even in the presence of exogenous nitrogen. Such strains could be used in commercial applications to supply fixed nitrogen to cereal crops.

Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis.

BACKGROUND: Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. METHODS: Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis. RESULTS: A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 µM at 48 h and 0.1 µM at 72 h) compared with parental PC-9 (IC50: 0.75 µM at 48 h and 0.027 µM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9. CONCLUSION: Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

An Interdisciplinary Review of Surgical Data Recording Technology Features and Legal Considerations.

Surgical data recording technology has great promise to generate patient safety and quality data that can be utilized to potentially reduce medical errors. Variations of these systems aim to improve surgical technique, develop better training simulation, and promote adverse event investigation similar to the aims of black box technology utilized in other industries. However, many unknowns remain for surgical data recording utilization in operating rooms and clinical settings in the United States. This includes the need to appropriately design systems so they collect meaningful and useful data that can be discussed by surgical team members in an open and safe environment to optimize clinical care processes. In order to better understand the clinical and regulatory environment for surgical data recording systems, we conducted an interdisciplinary review to identify key technology approaches, and assess legal and regulatory implications associated with this potentially disruptive technology. We found technology ranging from audio and visual data, to systems utilizing mobile applications, and kinematic data capture. The data collected present legal questions over ownership of information and privacy, along with regulatory issues at the federal and state levels. The benefits of these data should be balanced with the need to develop appropriate policies and regulations that protect the interests of both clinicians and patients in order to encourage further innovation and better realize the potential of surgical data recording technology to improve clinical decision making and patient safety outcomes.